The goals of this study were twofold: (1) to determine the in vivo dose-response relationship in the conscious, unstressed rat between the plasma insulin concentration and total body glucose uptake, and between plasma insulin and suppression of endogenous glucose production; and (2) to develop a physiologic compartmental model to describe the kinetics of plasma glucose in the rat in the basal state. In order to perform repeat insulin clamp studies in the same rat, chronic catheters were implanted in the aortic arch (via the carotid artery) and in the cardiac atrium (via the jugular vein), exteriorized, and fixed to the back of the skull with a dental cement cap. Insulin was infused at rates of 1.2, 2.4, 4.8, 12, and 24 mU/min · kg, and the plasma glucose was held constant at the basal level by a variable glucose infusion (euglycemic insulin clamp). The resulting steady-state plasma insulin concentrations ranged from 40 to 1,300 μU/mL. The dose-response curve for glucose uptake was sigmoidal in shape: in the basal state, total glucose utilization averaged 6.8 mg/min · kg at an insulin concentration of 9 μU/mL, half-maximal glucose uptake (18.3 mg/kg · min) occurred at a plasma insulin concentration between 70 and 80 μU/mL, and maximal uptake (36.6 mg/kg · min) was seen at an insulin level in excess of 100 μU/mL. Residual endogenous glucose production was evaluated by a prime-continuous infusion of (3-3H)-glucose. The dose-response curve for suppression of endogenous glucose output also was sigmoidal: basal glucose production in the fasting state (6.8 mg/kg · min) suppressed by 71% at the lowest (1.2 mU/kg · min) insulin infusion, and by greater than 90% in animals receiving 2.4, 4.8, or 12 mU/min · kg infusions. Half-maximal inhibition of glucose production occurred at an insulin concentration between 30 and 40 μU/mL. In additional studies bolus injections of tritiated glucose were rapidly administered through the venous catheter, and the time-course of plasma radioactivity was monitored closely for 120 minutes. The plasma clearance rate of glucose determined by this method was 5.2 ± 0.7 mL/min · kg. The initial distribution volume was 159 ± 12 mL/kg. Two exponential components were identified in the tracer disappearance curve of each animal. Based on stringent statistical criteria, the data were fitted to a two-compartmental model. The total volume of the glucose space in this model was calculated to be 273 ± 16 mL/kg and contained a total amount of glucose equal to 307 ± 16 mg/kg. Of this, 179 ± 8 mg/kg resided in the rapidly exchanging compartment (assumed to be the insulin-independent pool), v only 128 ± 8 mg/kg in the insulin-dependent pool. In conclusion, in the rat as in man the curve relating glucose uptake to plasma insulin concentration is sigmoidal in shape, linear and steep at insulin concentrations between 40 and 100 μU/mL; maximal insulin effect resulted in a sixfold stimulation of glucose metabolism above baseline. Hepatic glucose production is completely suppressed at insulin concentrations greater than 70 μU/mL, with half-maximal suppression occurring at insulin concentrations of 30 to 40 μU/mL.
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism